8 Moleküler Hedeflenmiş TedavilerBiological TherapiesMoleküler Hedeflenmiş TedavilerTirozin Kinaz İnhibitörleriProteasom InhibitörleriMonoklonal Antikorlar (MoAbs)Slide 29These are chemical molecules developed to act at the cellular level. They interact with various receptors or enzymes within cells to affect cellular function. MoAbs may be viewed as both biological and molecular targeted therapies.Reference: Grabenstein, 2004

10 Imatinib Mesylate (Gleevec®)Biological TherapiesImatinib Mesylate (Gleevec®)İmatinib mesylate (Gleevec) philadelphia kromozomu pozitif olan KML hastalarında (ilk seçenek ve relaps) ve gastrointestinal stromal tümörlerde (GIST) kullanım endikasyonu vardır.Ağızdan alınabilen küçük organik bir moleküldürSlide 32Imatinib mesylate also inhibits receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem cell factor (SCF), c-kit, and inhibits PDGF- and SCF- mediated cellular events. These actions are responsible for its efficacy in GIST.In clinical trials, imatinib mesylate as a single agent demonstrated longer progression-free survival in patients with chronic myeloid leukemia than did the combination of interferon-alpha plus cytarabine. Seventy percent of the interferon-treated patients crossed over to the imatinib mesylate arm during the trial or dropped out of therapy because of the high toxicity of the interferon therapy. Ninety percent of the imatinib mesylate patients remained on therapy for the duration of the study, and reported no toxicities severe enough to warrant stopping therapy.Effectiveness (hematologic response) has varied with dosage, and response rates have been higher in patients who have not been previously treated with another therapy. Overall, imatinib appears to lengthen time to progression and overall survival in patients with CMLIn patients with GIST – kit-positive unresectable and/or metastatic malignant – between 33% and 43% of patients demonstrated a partial response.References: Novartis, 2004Gleevec® (Novartis)

12 Imatinib Mesylate: Yan etkilerBiological TherapiesImatinib Mesylate: Yan etkilerEn yaygın yan etkiler:Hafif orta ödem,Bulantı, kusma,Kas krampları,Kemik ağrısı,İshal,DöküntüDaha az görülen yan etkiler:Anemi,Nötropeni,Trombositopeni,Karaciğer toksisitesi,İlaç etkileşimleriSlide 34Patients should be weighed and monitored regularly for signs of fluid retention. It can most often be managed with diuretics.Imatinib mesylate should be taken with food to minimize GI irritation.Imatinib mesylate has been associated with anemia, neutropenia, and thrombocytopenia, and complete blood counts should be performed weekly for the first month, biweekly in the second month, and periodically thereafter.Liver toxicity, sometimes severe, has occurred with imatinib mesylate. Patients should be monitored and dosage reduced or stopped if abnormalities appear.There are several known drug interactions with imatinib: physicians and nurses should be aware of patient usage of any other substance.Reference: Novartis, 2004Neumega® (Wyeth-Ayerst)

13 Biological TherapiesGefitinib (IRESSA®)Bir aniloquinozol olup HER 1-EGFR (epidermal büyüme faktör reseptörü) nü içeren transmembran reseptörleri ile ilişkili hücre içi trozin kinaz fosforilizasyonunu bloke ederek tümör hücresinin büyümesini ve çoğalmasını engeller.Slide 35Gefitinib was approved for use in patients with non-small cell lung cancer as third-line therapy. Patients had previously been treated with at least two other regimens; 25% had undergone four or more. The overall response rate at either 250 or 500 mg per day was about 10%. There appeared to be substantial differences in response rates in subsets of patients, with higher response rates for women (about 17%) and patients with adenocarcinoma, and with lower response rates seen in men (about 5%) and smokers.In combination with platinum-based chemotherapy, gefitinib did not demonstrate any increase in tumor response rate, time to progression, or overall survival.Gefitinib was approved on the FDA’s accelerated program that permits patients with very severe conditions to receive therapies prior to the usual extent of testing. Thus, it continues in clinical trials.While gefitinib has been approved as third-line therapy in non-small cell lung cancer, it remains in investigational trials in NSCLC as well as other forms of cancer.Reference: AstraZeneca, 2003IRESSA® (AstraZeneca)

16 Gefitinib: Yan EtkilerBiological TherapiesGefitinib: Yan EtkilerEn yaygın yan etkiler:Hafif orta derecede ishal,Akne benzeri döküntüCilt reaksiyonlarıBulantı ve kusmaDaha az yaygın ancak ciddi ve ölümcül olabilen yan etki: intestisyel akciğer hastalığıSlide 37Common side effects reported with gefitinib in clinical trials were nausea, vomiting, diarrhea, rash, acne, and dry skin. Gefitinib may cause fetal harm when administered to pregnant women.A significant safety concern associated with gefitinib did emerge during the approval process. Reports from Japan described the occurrence of serious and sometimes fatal interstitial lung disease (ILD) in patients treated with it. The FDA extended its review of gefitinib by three months to review these reports. After careful review of information from all sources, including a comprehensive analysis of updated toxicity information from clinical trials and the gefitinib expanded access program, involving approximately 23,000 patients, FDA determined that the incidence of ILD was approximately 2% in the Japanese experience and approximately 0.3% in the United States expanded access program, with about 1/3 of affected patients dying from this toxicity. FDA believes that this rare but serious toxicity of gefitinib does not outweigh the benefits demonstrated in patients with advanced NCSLC.Reference: AstraZeneca, 2003; FDA, 2003IRESSA® (AstraZeneca)

17 Proteazom İnhibitörleriBiological TherapiesProteazom İnhibitörleriProteazom (hücre işlevi ve büyümesini düzenlemede önemli bir rol oynayan enzim) aktivitesini engelleyen protezom inhibitörüdürProteasomlar hücre siklusu, yeni kan damarı oluşumu, hücre adhezyonu, sitokin üretimi ve apopitoz da rol oynarBloke edildiğinde/engellendiğinde kanserli hücre ölümü meydana gelirSlide 38Proteasomes are enzymes that “chop” proteins into smaller pieces inside a cell. Once a protein has been chopped up, the pieces can be transported to the cell surface for “recognition” by ligands or receptors. Several different cell cycle processes are regulated through this proteasome mediation.Evidence suggests that it serves both as a disposal system for damaged cellular proteins and as a mechanism for degrading short-lived regulatory proteins that govern cellular functions such as the cell cycle, cell growth, and differentiation. Because these processes or their dysregulation are crucial steps in tumor formation, the proteasome pathway is a logical target for therapeutic intervention.Proteasome inhibition appears to: - Impede cancer cell proliferation by preventing the breakdown of certain valuable proteins and transcription factors that are known to hinder cancer cell growth. - Reduce the survivability of cancer cells by inactivating certain genes and proteins that help cancer cells survive chemotherapy. - Cause cancer cell death by producing extreme cellular stress in tumor cells through disruption of cell proliferation.References: Sompayrac, 1999; Millennium, 2004

21 Monoklonal Antikor TürleriBiological TherapiesMonoklonal Antikor Türleriİnsan-umabFare-momabÖzdeş (Chimeric)-ximabİnsanlaştırılmış-zumabSlide 43Murine monoclonal antibodies are derived from mice. Mouse antibodies have a very short half-life in the human body, are not as effective as human antibodies in eliciting an effector response from the CDC and ADCC systems, and can cause the development of human anti-mouse antibodies (HAMA) that neutralize and render the mouse antibodies ineffective against the tumor. Mouse antibodies are usually named with the suffix “-momab.” An example of a mouse antibody is ibritumomab tiuxetan (Zevalin®).To overcome the limitations of mouse monoclonal antibody, scientists have engineered antibodies that have more human and fewer murine components. This allows better interaction with human effector cells and thus better cell killing, fewer side effects, and a longer serum half-life.Three types of “engineered antibodies” are described in this slide.Chimeric antibodies: The Fc portion of the human antibody is fused to the Fab portion of the mouse monoclonal antibody. The mouse portion recognizes the antigen and the human portion recruits the immune system. Chimeric antibodies are usually named with the suffix “-ximab.” An example of a chimeric antibody is rituximab (Rituxan®).Humanized antibodies: Only a very small part of the Fab portion of the mouse antibody is fused to a human antibody, making the antibody primarily human (95-98%). The monoclonal antibody retains its ability to recognize and bind to the target antigen (through the mouse portion), provides effective CDC/ADCC activation (through the human portion), and limits the potential neutralizing response to the antibody. Humanized antibodies are usually named with the suffix “-zumab.” Examples of humanized antibodies are trastuzumab (Herceptin®) and alemtuzumab (Campath®).In fully human antibodies, the entire antibody has been engineered to contain only human antibody gene sequences. Many of these types of antibodies are still in developmental stages. Human antibodies are usually named with the suffix “-umab.” An example of a fully human antibody is adalimumab (Humira™), used in treating rheumatoid arthritis.References: Cheng et al., 2000; LoBuglio et al., 1992; Rieger, 2001; Yarbro et al., 2000; Cheson, 2001.

24 Rituximab: Etki MekanizmasıBiological TherapiesRituximab: Etki MekanizmasıB-Cell non-Hodgkins Lymphoma Targets CD20 AntigenSlide 49B-cell lymphomas have well-defined surface antigens known as CDs (clusters of differentiation). CDs, such as CD20, play a role in normal B-cell maturation and survival, which makes them ideal candidates for monoclonal antibody therapy.The CD20 antigen is an ideal target antigen for monoclonal antibody therapy for several reasons:CD20 is present on greater than 90% of B-cell lymphomas.CD20 is found on normal B-cell precursors and mature B cells, but not on stem cells, normal plasma cells, or other nonlymphoid normal tissues. This allows for normal immunoglobulin production and B-cell repopulation.CD20 may play a role in regulating tumor cell growth.References: Genentech, 2002a; Wood, 2001; Alas, 2001Rituxan™ (Genentech)

26 (MaBthera®, Rituximab) İnfüzyonla İlişkili Yan EtkilerBiological Therapies(MaBthera®, Rituximab) İnfüzyonla İlişkili Yan EtkilerHafif-Orta Ciddi GecikmişAteş Bronkospazm Hafif lökopeniTitreme/ katılık Hipotansiyon Hafif trombositopeniBulantı Anjiyo-ödem Hafif nötropeniHalsizlik Aritmi Hafif anemiBaş ağrısıKaşıntı, döküntü, ürtikerBurun akıntısıMyalji/atraljiRituximab side effects are generally mild to moderate, most occurring during the first infusion, especially the first 1 to 3 hours of the first infusion. Therefore, close observation of the patient during the first 1 to 3 hours is necessary. The frequency and severity of the infusion-related effects are affected by the rate of infusion, by the health and concomitant illnesses of the patient, and possibly by the presence of tumor cells in circulation.Infusion-related effects include temperatures >38ŞC, chills, rigors, urticaria, rhinitis, nausea, diarrhea, and myalgia/arthralgia. Uncommon but potentially more severe events have included bronchospasm, hypotension, and angioedema. Arrhythmia has recurred in patients with a history of this disorder.Potential allergic reactions and anaphylaxis have not been reported, but patients should be assessed and treated for these life-threatening events. The treatment of infusion-related effects is to stop the infusion and restart it when the side effects have been successfully treated. Subsequent doses are usually well tolerated without major side effects.

33 Bevacizumab (Avastin™)Biological TherapiesBevacizumab (Avastin™)% 93 insan, %7 fareVEGF bağlanırVEGF ve reseptörlerine bağlanarak VEGF yoluyla oluşan anjiojenezisi engellerSlide 60Bevacizumab is a recombinant humanized monoclonal antibody against the VEGF molecule. It is 93% human and 7% murine. Because humanized antibodies contain a much smaller percentage of mouse protein than chimerized antibodies, they are thought to be less likely to trigger an unwanted immune response.Bevacizumab recognizes all forms of VEGF and binds to the VEGF molecule with high affinity. The antibody prevents VEGF from binding to its natural receptors, thus inhibiting VEGF-induced angiogenesis. This image depicts the binding of VEGF with bevacizumab thereby minimizing the amount of circulating VEGF available to bind to its receptors and activate the angiogenesis process.The terminal half-life of bevacizumab is days.Bevacizumab, in combination with IV 5-fluorouracil chemotherapy, has been approved for first-line treatment of patients with metastatic carcinoma of the colon and rectum.Reference: Hurwitz, Fehrenbacher, Cartwright, et al., 2003Avastin™ (Genentech)